Exercise‐induced appetite suppression: An update on potential mechanisms

Abstract The first systematic reviews of the effects of exercise on appetite‐regulation and energy intake demonstrated changes in appetite‐regulating hormones consistent with appetite suppression and decreases in subsequent relative energy intake over a decade ago. More recently, an intensity‐dependent effect and several potential mechanisms were proposed, and this review aims to highlight advances in this field. While exercise‐induced appetite suppression clearly involves acylated ghrelin, glucagon‐like peptide‐1 may also be involved, though recent evidence suggests peptide tyrosine tyrosine may not be relevant. Changes in subjective appetite perceptions and energy intake continue to be equivocal, though these results are likely due to small sample sizes and methodological inconsistencies. Of the proposed mechanisms responsible for exercise‐induced appetite suppression, lactate has garnered the most support through in vitro and in vivo rodent studies as well as a growing amount of work in humans. Other potential modulators of exercise‐induced appetite suppression may include sex hormones, growth‐differentiation factor 15, Lac‐Phe, brain‐derived neurotrophic factor, and asprosin. Research should focus on the mechanisms responsible for the changes and consider these other modulators (i.e., myokines/exerkines) of appetite to improve our understanding of the role of exercise on appetite regulation.


| INTRODUCTION
Over the past three decades, a host of research studies have assessed the effect of acute exercise on appetite regulation (Stensel, 2010).While a detailed description of the control of appetite is beyond the scope of this review and previously well explained (Murphy & Bloom, 2006), a brief overview is summarized in Figure 1.The regulation of energy intake is a complex system involving behavioral, environmental, and physiological factors (King et al., 2012) however, this review will focus on the physiological.On a meal-to-meal basis, the physiological regulation of energy intake involves fluctuations in orexigenic (appetite-stimulating) and anorexigenic (appetite-suppressing) peripheral appetite hormones (Cummings & Overduin, 2007).Many of these hormones circulate in active and inactive forms, where the active forms such as acylated ghrelin, glucagon like peptide 7-36/7-37 (GLP-1), and peptide tyrosine tyrosine 3-36 (PYY) are more important in appetite regulation (Chelikani et al., 2005;Orskov et al., 1993;Yang et al., 2008).Changes in these hormones can alter perceptions of appetite by acting on specific brain regions (hypothalamus/brainstem) altering the release of neuropeptides responsible for changes in feeding behavior (Harrold et al., 2012;Parker & Bloom, 2012).
Several reviews (Hazell et al., 2016;Schubert et al., 2013Schubert et al., , 2014) ) were pivotal in summarizing the relationship between acute exercise and appetite.A decade ago two meta-analyses demonstrated energy intake is not increased postexercise to compensate for exercise energy expenditure (Schubert et al., 2013) and these changes involve decreases in acylated ghrelin as well as increases in PYY and GLP-1 (Schubert et al., 2014).While other peripheral hormones (e.g., pancreatic polypeptide, leptin, cholecystokinin) are involved in the regulation of appetite, the previous meta-analysis focused on acylated ghrelin, PYY, and GLP-1 as these are most often assessed with exercise.The influential research included in these two meta-analyses focused on the postexercise responses, and a subsequent review highlighted an intensity-dependent role of exercise as well as proposed several physiologically plausible mechanisms unique to higher intensity exercise that may be responsible for the changes in appetite-regulating hormones (Hazell et al., 2016).These reviews (Hazell et al., 2016;Schubert et al., 2013Schubert et al., , 2014) ) highlighted that the duration of exercise does not appear to be important and duration has received little attention since and will not be discussed.This review will update these key exercise and appetite reviews published nearly a decade ago (Hazell et al., 2016;Schubert et al., 2013Schubert et al., , 2014) ) and highlight current advances and future directions.

| THE APPETITE RESPONSE TO EXERCISE
Acute bouts of exercise (aerobic and resistance) can create an energy deficit (Schubert et al., 2013) involving changes in key appetite-regulating hormones (Schubert et al., 2014).While a necessary first step in summarizing evidence regarding exercise and appetite, these reviews did not include exercise intensities above 80% maximal oxygen consumption (VȮ 2max ), characterized as vigorousintensity continuous training, high-intensity interval training (HIIT), or sprint-interval training.A thorough description of these protocols is available elsewhere (Coates et al., 2023).Additionally, both total and active forms of the appetite-regulating hormones were included and research focusing on the active forms which are more physiologically relevant, will be necessary to continue improving our understanding of the effects of exercise on appetite regulation (Chelikani et al., 2005;Orskov et al., 1993;Yang et al., 2008).Therefore, this section aims to summarize recent developments over the last decade that have improved our understanding of how exercise alters appetite (Figure 2).

| PROPOSED MECHANISMS
In 2016, eight mechanisms potentially involved in the exercise-induced changes in appetite-regulation were proposed (Hazell et al., 2016).Here we provide updates regarding lactate, IL-6, temperature, and blood glucose, while the other mechanisms have received little attention in the past decade and future research remains warranted.

| Lactate
Lactate has garnered the most attention and it's role has been recently reviewed (McCarthy et al., 2020).Causative evidence from rodent models demonstrates peripheral and central lactate administration (i.e., infusion or injection) alter both peripheral (Engelstoft et al., 2013) and central (Cha & Lane, 2009;Chen et al., 2023;Ou et al., 2019;Torres-Fuentes et al., 2019) appetite pathways involved in reductions in energy intake (Cha & Lane, 2009;Chen et al., 2023;Lam et al., 2008;Langhans et al., 1985;Nagase et al., 1996;Silberbauer et al., 2000).Lactate has been infused in humans in two studies (increasing lactate ~1.2-2.5 mmol•L −1 ; similar to increases following low-intensity exercise) where one study demonstrated lower energy intake (~1046 kJ) from an ad libitum meal compared to a saline infusion when participants were in an euglycemic state (Schultes et al., 2012) and the other demonstrated reduced acylated ghrelin concentrations, but no concomitant change in hunger/satiety (Pedersen et al., 2022).Exercise studies using both aerobic (Islam et al., 2017;McCarthy et al., 2023;Sim et al., 2014;Vanderheyden et al., 2020) and RT (Freitas et al., 2020;Liu et al., 2023;McCarthy et al., 2024) demonstrate greater lactate accumulation (≥2-2.5 mmol•L −1 ) aligns with suppressed subjective appetite perceptions and/or energy intake likely via changes in appetite-regulating hormones.One of the most compelling studies in humans assessing lactate's role in appetite used a unique design where participants ingested sodium bicarbonate pre-exercise allowing increased lactate accumulation during exercise and examined it's effects on appetite-regulating parameters.The exercise sessions were identical so any differences between sessions could be attributed to greater lactate accumulation.Greater blood lactate accumulation (+2.7 mmol•L −1 ) was achieved with sodium bicarbonate ingestion coinciding with ~30% lower acylated ghrelin concentrations and tended to reduce subjective appetite perceptions (~20%) compared to placebo (Vanderheyden et al., 2020).Recent evidence in rodent models (Lund et al., 2023) using a series of well-designed experiments disputes lactate's potential role and suggests it is the high osmolarity of the injected/infused lactate solution that leads to the reductions in energy intake in rodent models, not the lactate itself.While this data (Lund et al., 2023) suggests the reductions in energy intake are due to the high osmolarity of the solutions causing malaise and not lactate, it does not account for the changes in peripheral or central appetite pathways that have been demonstrated in vitro and in vivo (Cha & Lane, 2009;Chen et al., 2023;Engelstoft et al., 2013;Ou et al., 2019;Torres-Fuentes et al., 2019).Perhaps injecting/infusing lactate may not be the most effective method to study lactate's role in appetite regulation unless the osmolarity of the lactate and placebo solutions are matched.Additionally, the exogenous administration of lactate does not reflect that natural efflux of lactate from skeletal muscle.More causative work is required to fully elucidate lactate's role on appetite and confirm proposed mechanisms.

| Interleukin-6
IL-6 has received attention as a potential mechanism for exercise-induced appetite suppression as it's production and release is closely related to exercise intensity (Ostrowski et al., 2000;Pedersen & Fischer, 2007), duration (Ostrowski et al., 1998;Pedersen & Fischer, 2007), and the amount of muscle mass involved (Pedersen & Fischer, 2007).Early evidence supports a role in appetite regulation as previously reviewed (Ellingsgaard et al., 2011;Hazell et al., 2016;Kahles et al., 2014;Shirazi et al., 2013), but despite these promising results more recent work has been contradictory.Incubating GLP-1 producing cells (GLUTag cells) with IL-6 had no effect on GLP-1 production and infusing IL-6 into perfused mouse small intestine had no effect on GLP-1 release (Christiansen et al., 2018).High doses of IL-6 have been shown to suppress ghrelin mRNA and protein expression in pancreatic cell lines (Chew et al., 2014;Lao et al., 2013) though no work has followed up on this.In humans, IL-6 was moderately correlated with GLP-1 (no relationship with ghrelin) following acute bouts of MICT, VICT, and SIT in young normal weight males (Islam et al., 2017), though in young lean sedentary males as well as those experiencing obesity there was no effect of exercise-induced or adiposity-related IL-6 on GLP-1, acylated ghrelin, or other appetite markers (Bornath et al., 2023).Taken together, IL-6's potential role in appetite regulation is still unclear with inconclusive results in vivo and in vitro.Additionally, IL-6 release with exercise may be driven by lactate (Hojman et al., 2019) making it difficult to discern it's role.

| Temperature
The role of temperature has garnered attention as a potential mechanism in appetite regulation in the past decade (Brobeck, 1948;Hazell et al., 2016), and a recent meta-analysis revealed a modest orexigenic effect of cold exposure and a small anorexigenic effect of heat exposure (Millet et al., 2021).The exact mechanisms eliciting these responses are unclear and recent studies on environmental temperature at rest (Zakrzewski-Fruer et al., 2021) or following exercise (Kojima et al., 2018;Laursen et al., 2017) demonstrate increased acylated ghrelin following exercise in cold temperatures but no effect on total GLP-1 or total PYY (Mandic et al., 2019).Future work should look to explore the potential mechanisms involved in how changes in body/environmental temperature are involved in the appetite-regulatory response.

| Blood glucose and insulin
Changes in blood glucose and insulin have long been hypothesized to regulate appetite postprandially (Campfield & Smith, 2003;Mayer, 1955) as postprandial glycemic dips predict increases in appetite and energy intake (Wyatt et al., 2021) and insulin has been proposed to inhibit ghrelin secretion (Gagnon & Anini, 2012).While high blood glucose can attenuate ghrelin secretion from gastric mucosal cells in culture (Sakata et al., 2012) and intestinal glucose absorption stimulates GLP-1 release from enteroendocrine cells (Lu et al., 2021), whether brief (≤30 min) increases in blood glucose and insulin follow higher-intensity exercise (Peake et al., 2014;Vincent et al., 2004) are involved in exercise-induced appetite suppression is unclear.Preliminary work from our group suggests increases in glucose postexercise do not contribute to exercise-induced appetite suppression as despite similar increases in plasma glucose following MICT and SIT, acylated ghrelin and subjective appetite were suppressed following SIT only, though MICT increased GLP-1 (Bornath et al., n.d.).Insulin decreased following the standardized meal with no differences between sessions (Bornath et al., n.d.).It is plausible that blood glucose and insulin are important regulators postprandially but systemic metabolic changes during exercise override their effects, though more work is necessary to fully elucidate their role.
The remaining proposed mechanisms (redistribution of blood flow, sympathetic nervous system activity, gastrointestinal motility, and free fatty acid concentrations) have garnered little attention despite being implicated as potential mechanisms for exercise-induced appetite suppression.More work is needed to determine whether they are important and enhanced understanding of the potential mechanisms will be helpful in understanding the variability associated with exercise-induced changes in appetite regulation (Hazell et al., 2016).

| FUTURE DIRECTIONS
There are additional potential modulators that may be involved in exercise-induced appetite suppression including sex hormones, recently identified appetite hormones, as well as "myokines" and "exerkines" (Figure 3).

| Sex hormones
A majority of research (~85%) on exercise and appetite included only males as the menstrual cycle has been viewed as a confounding factor as opposed to a relevant physiological modulator of appetite.It has been suggested that estradiol (E 2 ) (Butera, 2010;Sinchak & Wagner, 2012) may be appetite-inhibiting while progesterone is appetitestimulating solely in the presence of E 2 (Butera, 2010;Hirschberg, 2012) and this has been supported by research demonstrating energy intake increases during the LP compared to the FP (Gorczyca et al., 2016;Hirschberg, 2012;Tucker et al., 2024).Only two studies have compared exercise-induced appetite suppression in premenopausal females in the FP and LP.The first showed no differences in acylated ghrelin, total PYY, appetite perceptions, or energy intake following an acute bout of MICT (Kamemoto et al., 2022).The second study demonstrated a blunted acylated ghrelin response in the LP following an acute bout of VICT with no differences in active PYY, active GLP-1, or appetite perceptions, though there was increased energy intake in the LP (Moniz et al., 2023).These differences may be due to methodological differences, as participants in the first study arrived at the laboratory fasted and were not fed for several hours following exercise resulting in ~16 h without food (Kamemoto et al., 2022), whereas in the latter participants were fed pre-exercise upon arrival at the laboratory (Moniz et al., 2023).Taken together, it is possible that the menstrual cycle may influence this response, though there is limited research investigating the influence of ovarian hormones on the appetite-specific response to exercise and more work is warranted.

| Growth differentiation factor 15
Growth differentiation factor 15 (GDF15) is a stress response cytokine (Tsai et al., 2018) released from a variety of tissues (i.e., liver, kidney, lung, intestines, and placenta) where pharmacological doses can suppress energy intake and reduce body weight (Emmerson et al., 2017;Hsu et al., 2017;Mullican et al., 2017;Yang et al., 2017).A potential role in exercise-induced appetite suppression has been suggested as prolonged exercise (>2 h in duration at moderate-vigorous intensities) increases circulating concentrations (~400%-500%) similar to those associated with pathological conditions or attained following metformin treatment, though this response is lost when exercise duration is shorter (≤1 h at moderate-vigorous intensities) (Klein et al., 2021(Klein et al., , 2022;;Kleinert et al., 2018).GDF15's potential role in appetite was recently reviewed (Klein et al., 2022) and it is unclear whether it contributes to exercise-induced appetite suppression as changes in GDF15 postexercise have yet to demonstrate reductions in food intake (Klein et al., 2021).While supraphysiological endogenous doses of GDF15 can reduce food intake and body weight, more work is required to determine if it is involved in exercise-induced appetite suppression.

| Lac-Phe
A recent advancement related to lactate's potential role in appetite regulation is linked to a lactate derived metabolite N-lactoyl-phenylalanine (Lac-Phe), which has been shown to be one of the most highly circulating metabolites following exercise in mice and humans (Li et al., 2022).Acute Lac-Phe injection reduces food intake in dietinduced obese mice by ~50% and daily injections reduce body weight by ~7% over a 10-day period (Li et al., 2022).This dose was ~100fold greater than circulating concentrations following exercise (Lund et al., 2022) questioning whether physiological doses have appetite-suppressing effects.Acylated ghrelin concentrations 30 min following Lac-Phe injection were ~ 50% lower compared to a saline injection, though the sample size was only 3 mice, and no p-value was provided.Though it appears Lac-Phe may affect acylated ghrelin concentrations, a mechanism has yet to be established as to how Lac-Phe suppresses appetite (Lund et al., 2022), thus more work is needed to determine whether physiological concentrations of Lac-Phe produced during acute exercise are capable of suppressing appetite and the potential mechanisms involved.

| Brain-derived neurotrophic factor
Brain-derived neurotrophic factor (BDNF) is a neurotrophin expressed in several key areas of the brain that plays a key role in synaptic plasticity as well as neuronal survival and function (Patapoutian & Reichardt, 2001;Poo, 2001).It has been implicated in appetite (Rios, 2013) as central administration reduces food intake (~94%) and body weight (~32%) in rodents (Pelleymounter et al., 1995), and BDNF knockout mice develop hyperphagia and obesity (Fox et al., 2013).While peripheral concentrations of BDNF increase postexercise (~13%-190%) on an intensitydependent basis in humans (Ceylan et al., 2023;Marston et al., 2017;Rasmussen et al., 2009;Reycraft et al., 2020), no study has explored it's relevance to appetite in humans by assessing subjective appetite perceptions or energy intake (ad libitum or free-living) in conjunction with BDNF.It appears BDNF's effects on appetite occur solely in the brain (Rios, 2013) making it difficult to assess in humans, though future work should attempt to use advanced techniques to determine if peripheral increases in BDNF contribute to exercise-induced appetite suppression in humans.

| Asprosin
Asprosin is a recently discovered fasting-induced glycogenic hormone released from white adipose tissue (Romere et al., 2016).Adults experiencing obesity and obese mice have greater concentrations of fasting asprosin compared to their lean counterparts (Ceylan et al., 2023;Duerrschmid et al., 2017;Romere et al., 2016) and subcutaneous administration of asprosin to mice increases food intake via activation of AgRP neurons and inhibition of POMC neurons that were prevented with ablation of AgRP neurons (Duerrschmid et al., 2017).Exercise (MICT and HIIT) appears to reduce asprosin concentrations (~20%-24%) in both normal weight and individuals living with obesity independent of intensity (Ceylan et al., 2020(Ceylan et al., , 2023) ) though a single supramaximal sprint found no change in males but a small increase in females (Wiecek et al., 2018).None of the studies that have assessed changes in asprosin have measured other outcomes related to appetite (i.e., appetite perceptions or energy intake) making it difficult to discern asprosin's role in exercise-induced appetite suppression in humans.

| CONCLUSION
The field of exercise and appetite-regulation is still growing and most evidence suggests exercise-induced appetite suppression via changes in peripheral appetite-regulating hormones, mostly acylated ghrelin, and potential reductions in subsequent energy intake.Small samples sizes (n = 8-12) are an issue as most studies are powered to detect changes in peripheral appetite-regulating hormones but not subjective measures of appetite perceptions or energy intake.It is important that this field continues to progress using rigorous approaches such as sample size calculations, clinical trial registration (where applicable, see (Richter et al., 2024) for a commentary on this), and sex-based comparisons to answer important questions.The next steps in exercise and appetite-regulation should continue to focus on the mechanisms responsible for the changes and consider the modulating effects of sex hormones, and other myokines/exerkines in studies aimed at improving our understanding of how exercise can suppress appetite.

AUTHOR CONTRIBUTIONS
All authors were involved in all aspects of this

F
I G U R E 3 Overview of potential modulators involved in exercise-induced appetite suppression.Green arrows represent the hypothesized effect on appetite.Blue arrows indicate that human data shows no effect (sideways) or an effect (downward) and a question mark indicates data is unclear or lacking.